tbuckley/cabot-search huggingface dataset:
CyberKnife Stereotactic Radiosurgery for Spinal Haemangioblastoma: A Single Centre Experience
Authors: Kieran Palmer, Gemma Whitelaw, Anant Krishnan, Chris Dean, Paolo Jose De Luna, Adam Mitchell, Nick Plowman, Rachel Lewis
Journal: Neuro-Oncology (2022)

Abstract AIMS ‘CyberKnife’ stereotactic radiosurgery (SRS) is increasingly being used as a treatment for spinal haemangioblastoma to avoid complex surgery, especially in patients with multi-focal tumours associated with von Hippel-Lindau syndrome (VHL). Here we present the outcomes of patients treated in our centre. METHOD Retrospective review of patients treated at St Bartholomew’s Hospital, London. Assessment of radiological response was based upon RECIST criteria. The development of a symptomatic new or worsening cyst was included in the definition of progression when determining overall tumour control. Solid and overall tumour control rates were calculated using the Kaplan-Meier method. RESULTS 14 tumours in 10 patients were included. 70% of patients were male and 90% had VHL. 9 (64%) tumours had an associated cyst. The median (IQR) age at treatment was 45.5 (43.5 – 53). The median gross tumour volume was 0.355cc. Patients received a mean marginal prescribed dose of 9.6Gy in a single fraction (mean central dose 14Gy) – dose constrained by spinal cord tolerance. Mean follow up was 15.4 months. 7 patients’ symptoms improved or were stable and 3 worsened. Radiologically, 11 (78.6%) of tumours were stable or regressed, and 3 (21.4%) progressed. The 1-year solid tumour and overall tumour control rates were 92.3% and 75.7% respectively. All patients were alive at most recent follow up. 2 patients developed grade 1 adverse related events. CONCLUSION SRS is a safe and effective treatment modality for spinal haemangioblastoma. Further prospective randomised trials with longer follow up are required to determine the optimum management strategy.
Neurosurgically-Applied Chemotherapy for Childhood Brain Tumours Arising in the Posterior Fossa Using a Biodegradable Paste
Authors: Cara Moloney, Menelaos Mavromoustakos, Cameron Alexander, Ruman Rahman
Journal: Neuro-Oncology (2022)

Abstract AIMS This project aims to develop a local drug delivery system for treatment of childhood medulloblastoma (MB) and atypical teratoid/rhabdoid tumours (AT/RT), malignant brain neoplasms occurring in the posterior fossa for which prognoses remains poor. Our goal is to repurpose drug compounds reported as effective against MB and AT/RT, but which either cannot cross the blood-brain-barrier (BBB) or have not been assessed for localised delivery. We have developed a novel intra-cavity drug delivery system, consisting of polymer microparticles made from poly(DL-lactic-co-glycolic acid) and poly(ethylene glycol) (PLGA/PEG) which will be employed to release drugs over several weeks. METHOD Cell toxicity assays were undertaken using drugs of interest against an in vitro panel of relevant MB and AT/RT cell lines. PLGA/PEG paste incorporating the drugs were prepared and release kinetics assessed. RESULTS IC50 values of the drugs were assessed across all cell lines and a range of potencies were observed, with optimum conditions identified as dual treatments of PG545 (heparanse inhibitor) with CHIR99021 (glycogen synthase kinase-3 inhibitor) for MB and ribavirin (anti-viral) with CHIR99021 for AT/RT. Importantly, it was noted that the drugs retained their cytotoxicity following release from PLGA/PEG. Furthermore, release kinetics were finely tuned through careful control of the composition through addition of excipients and encapsulation of drugs in nanoparticles, and a library of formulations were prepared. CONCLUSION A local drug delivery system for MB and AT/RT has been developed and an optimum formulation, based upon in vitro cell assays and release kinetics, has been identified for in vivo efficacy studies in orthotopic models.
Management of Low-Grade Gliomas – Extent of Resection Matters But Not All Tumours Are Amenable to Surgery
Authors: Giannis Sokratous, Jill Sokratous, Ali Bakhsh, Andrew Brodbelt, Emmanuel Chavredakis, David Lawson, Jibril Farah, Aditya Shenoy, Chloe May, Michael Jenkinson, Shaveta Mehta
Journal: Neuro-Oncology (2022)

Abstract AIMS To present and review our experience in the management of low-grade gliomas. METHOD Retrospective case note review of all patients with WHO grade 2 glioma from 2011 to 2018 (based on WHO criteria at time of diagnosis). Data collected on demographics, presentation, location, initial management, histology, treatment, progression free (PFS) and overall survival (OS). RESULTS 130 eligible patients. Median follow 4.6 years (up to 10.5). Median age 40 years (range: 18-83). There were 70 (53.8%) astrocytomas, 44 (33.8%) oligodenrogliomas, 16 (12.3%) oligoastrocytomas. 66%(n=86) presented with seizures, 10.7%(n=14) with sensory symptoms, 8.5%(n=11) with speech disturbance, 5.3%(n=4) with motor symptoms and 12.3%(n=16) were identified incidentally. 50.1%(n=65) were frontal, 27.7%(n=36) temporal and 9.2%(n=12) parietal. 1st line treatment was resection in 70.7%(n=92), biopsy in 23.8%(n=31) and observation in 4.6%(n=6). 15.4%(n=20) received adjuvant radiotherapy alone and 6.1%(n=8) received adjuvant radiotherapy followed by chemotherapy . At first recurrence, 31.6%(n=12) received further surgery and 95%(n=38) received radiotherapy and/or chemotherapy . Median PFS from 1st line treatment 66, 44 and 33 months for gross total resection (GRT), subtotal resection (STR), and biopsy respectively. Overall survival was 95.1%, 79.3% and 69.% for GTR, STR and biopsy respectively. CONCLUSION Management of low-grade gliomas remains challenging. Extent of resection impacts prognosis but not all patients have gliomas amenable to surgery. The effects of chemoradiotherapy will be presented in future meetings as this is an ongoing project.
Novel Application of Polygenic Risk Scores Identifies Biomarkers for Early Detection of Glioma
Authors: Lily Andrews, Jamie Robinson, Kathreena Kurian, Siddhartha Kar
Journal: Neuro-Oncology (2022)

Abstract AIMS In the UK, brain, other CNS and intracranial tumours incidence rates are increasing with over 12,200 new cases diagnosed each year. The overall survival rate over 5 years in these tumours is approximately 12%. There is a need for predictive biomarkers to detect the presence of gliomas to improve prognosis for such patients. A novel modified Mendelian randomization (MR)-based technique has been proposed to discover predictive biomarkers for diagnostic applications. The aim of this project is to identify circulating blood biomarkers that are genetically liable to all gliomas, glioblastoma (GB), or non-GBs. METHOD We generated polygenic scores for genetic liability to glioma and a separate GWAS of plasma protein levels from the INTERVAL study. We used sensitivity analyses methods to further assess our findings. The results were then validated by the plasma pQTL GWAS data from the Fenland cohort. RESULTS We identified a potential blood biomarker called erythroblast membrane associated protein (ERMAP) which showed consistent results across all sensitivity analyses in our discovery cohort [β: -0.0778, P-value: 2.1E-04]. We identified that decreased levels of ERMAP [β: -0.078 SD of ERMAP abundance per SD increase in glioma risk, 95% confidence interval (CI) 0.037 to 0.119, P-value: 2.1E-04] in the blood are associated with increased risk of glioma. CONCLUSION ERMAP protein is found to have a potential genetic liability for all gliomas. Predictive biomarkers are novel to glioma research and could be important for diagnostic applications and population screening in early detection. However, further clinical research is required to validate these findings.
Glioma Espionage From Longitudinal CSF Proteomics
Authors: Cecile Riviere-Cazaux, Terry Burns
Journal: Neuro-Oncology (2022)

Abstract AIMS Rapid, detailed feedback is needed to understand the individualized biological impacts of novel glioma therapies. We are performing glioma biomarker discovery by serial cerebrospinal fluid (CSF) sampling from Ommaya reservoirs to determine how the CSF proteome can reveal early longitudinal intelligence regarding glioma status, biology, and therapeutic response. METHOD Global proteomic analysis of CSF was performed on the Somalogic platform – an aptamer-based technology for highly sensitive and specific analysis of over 7,000 proteins. Discovery analysis comprised of the top-500 ranked proteins in CSF from seven patients with high-grade gliomas (HGG) versus non-glioma controls. The top-500 HGG proteins were then preliminarily filtered to include only proteins that met two additional criteria of decrease with resection and increase with recurrence in individual paired patient samples. RESULTS Proteomic enrichment analysis revealed a conserved HGG CSF proteomic signature defined by 79 proteins, including ones known to be over-expressed in solid tumor malignancies, such as retinoblastoma binding protein 4, heat shock protein 90, and sorcin. The HGG proteomic signature was consistently enriched in an independent validation cohort consisting of 13 gliomas diverse in primary versus recurrent status, subtype, and grade, when compared to control CSF samples. Encouragingly, proteins in the HGG signature decreased in the two patients for whom CSF was collected prior to and after resection (both at POD16 and POD18) with decreased tumor burden. CONCLUSION Our data demonstrate the ability to gain detailed, individualized insights regarding glioma biology, tumor burden, and evolution through global CSF proteomics acquired from longitudinal access to gliomas via Ommaya reservoirs.
Treatment of Glioblastoma Multiforme at Progression or Recurrence: A Service Evaluation
Authors: Thomas Matthew Quarrell, Zack Millar, Gary Doherty, Rajesh Jena, Fiona Harris
Journal: Neuro-Oncology (2022)

Abstract AIMS After initial treatment, glioblastoma multiforme (GBM) invariably reoccurs or progresses. When this happens, there is no established standard of care and treatment choice is made on a case-by-case basis. In our service, there is a multidisciplinary approach to progression, with oncologists and surgeons cooperating closely. This means that our cohort is ideal for studying treatment at progression. METHOD We performed a retrospective cohort service evaluation on patients diagnosed with isocitrate dehydrogenase wildtype GBM over a 4-year, 5-month period. We focused on patients who had received Stupp regimen treatment. Analysis was though a cox-proportional hazard model with multiple imputation analysis for missing data when appropriate. RESULTS The variable most strongly correlated with the treatment chosen at progression was patient performance status (Kruskal Wallis chi-squared = 22.804, p=0.00014). Some variables, such as age at progression or initial surgical management, were unexpectedly not correlated with the chosen treatment. Of the possible treatments at progression, only surgical management approached borderline significance for increasing survival relative to best supportive care (p=0.06). Performance status had at most a moderate, non-significant impact upon survival post-progression. The MGMT methylation status of the tumour emerged as a powerful predictor of survival post-progression (p=0.01). CONCLUSION A range of variables are correlated with which treatment is chosen at progression, but they do not always relate to the post-progression survival. Of all treatments, we can only demonstrate surgical management as having an impact upon survival, suggesting a more moderate effect of medical therapies relative to best supportive care.
The Measurement and Reporting of Outcomes in Clinical Studies of Incidental and Untreated Meningioma Are Heterogeneous and Prevent Knowledge Progress: A Systematic Review
Authors: Christopher Millward, Abdurrahman Islim, Sumirat Keshwara, Nisaharan Srikandarajah, Andrew Brodbelt, Anthony Marson, Paula Williamson, Michael Jenkinson
Journal: Neuro-Oncology (2022)

Abstract AIMS There is increasing interest in the clinical management of patients with incidental and untreated intracranial meningioma. Determining balance between observation and intervention is a key research priority. However, heterogeneity of outcome measurement and reporting has hampered knowledge progress. This systematic review aimed to summarise the outcomes measured and reported in such studies. METHOD A systematic literature search was performed to identify published full-texts describing active monitoring of adult cohorts with incidental and untreated intracranial meningioma. Reported outcomes were extracted verbatim, along with an associated definition and method of measurement if provided. Deduplication, grouping, and classification of verbatim outcomes was performed to identify unique outcomes reported in the literature. RESULTS Thirty-three published articles and one ongoing study were included, describing 32 unique studies: retrospective n=27, cross-sectional n=3, prospective n=2. 271 verbatim outcomes were reported, of which 90 were defined. Following deduplication, 181 unique verbatim outcomes remained and were grouped into 53 unique ‘non-verbatim’ outcomes. Those reported most frequently included: volume of tumor n=18, growth of tumor n=30, absolute growth rate n=18, relative growth rate n=17, need for surgery n=21, and progression-free survival n=11. CONCLUSION Harmonisation of outcome measurement and reporting across clinical studies of incidental and untreated intracranial meningioma could facilitate knowledge progress for this priority research area. The unique outcomes identified from this systematic literature review will be prioritised through an eDelphi survey and consensus meeting of key stakeholders (including patients), in order to develop a Core Outcome Set (COS) for use in future clinical studies.
CONSENT - A Randomised Controlled Trial of Enhanced Informed Consent Compared to Standard Informed Consent to Improve Patient Understanding of Early Phase Oncology Clinical Trials – GBM Cohort (Nonrandomised) Analysis
Authors: Abhijit Pal, Robert Daly, Shybi Mohamedkhan, Rafael Grochot, Sarah Stapleton, Christina Yap, Dimitrios Magkos, Bindumalini Rao Baikady, Anna Minchom, Udai Banerji, Johann De Bono, Deme Karikios, Frances Boyle, Juanita Lopez
Journal: Neuro-Oncology (2022)

Abstract AIMS Early phase cancer clinical trials have become more complicated and patients often misunderstand their nature and purpose. CONSENT (NCT04407676) is a randomised controlled trial testing whether enhanced informed consent for patient education can improve comprehension – since patients with glioblastoma multiforme (GBM) have a higher rate of baseline cognitive impairment, we studied this group separately. METHOD GBM patients (from the ICE-CAP Phase 1 study - NCT03673787), underwent the schedule for the standard CONSENT arm - full length trial PIS, Quality of Informed Consent Questionnaire Parts A and B (QuIC-A and QuIC-B), experimental intervention (2 page study aid and 10 educational videos), and a repeat QuIC-A and QuIC-B. The primary endpoint for this subgroup was the difference in QuIC-A scores before and after the intervention using a paired t-test. RESULTS 6 patients with GBM were recruited - 3 did not complete any study questionnaires. The three pre intervention QuIC-A scores were 70, 81, 88, with a mean of 75 (unit reference 76). The three pre intervention QuIC-B scores were 69, 62, 75 with a mean of 69 (unit reference is 91). Only one patient completed the post intervention questionnaire - their QuIC-A score moved from 88 to 100. CONCLUSION This study demonstrates the significant difficulties in studying comprehension in patients with GBM considering early phase trials. There is a need for creative multi-modality solutions to provide information to GBM patients considering clinical trials, and novel tools to assess the effectiveness of these solutions.
Exploring a Link Between Alzheimer’s and Glioma by Investigating SORL1 Network
Authors: Kristy Montalbo, Emyr Bakker, Izabela Stasik, Christopher Smith
Journal: Neuro-Oncology (2022)

Abstract AIMS Use bioinformatics methods to identify and validate associated proteins and genes in the SORL1 network. Generate a bank of patient derived cells in association with the Royal Preston Hospital BTNW tissue bank. Explore identified targets from the bioinformatics in patient derived cells. METHOD Proteins and genes associated with SORL1 and SORLA were identified on GeneCards. Connectivity mapping of known and predicted interactions linked to SORL1 was explored in STRING. For clinical validation differential expression was investigated by comparing genomic data from GTEX and TCGA, available at Xenabrowser. For survival analysis Kaplan-Meier curves were generated on cBioPortal. The five most differently expressed novel targets are taken forward for laboratory experiments using western blots for protein quantification and immunocytochemistry to identify and visualise target proteins. RESULTS A total of 73 genes (30 from GeneCards and 43 from STRING) were obtained. 63 genes from the generated SORL1-related network were shown to be differentially expressed whilst 40 were significantly different between low-surviving patients and high-surviving patients. The top five associated proteins are CKAP4, CTNND1, FN1, HSPA12A and SORCS3. CKAP4, CTNND1 and FN1 are highly expressed in both glioma and glioblastoma, but low expressed in healthy tissue. HSPA12A is low expressed in cancerous brain tissue and highly expressed in healthy samples. SORCS3 is differentially expressed in healthy samples and glioma, but significantly low expressed glioblastoma. CONCLUSION This project provides insight into SORL1 molecular relationships and function in tissue, cultured cells and serum from a patient cohort including demographics, disease progression and site.
Core outcomes in Brain Tumour Trials – The COBra Study Review of Glioma Trial Registration Data
Authors: Ameeta Retzer, Elin Baddeley, Stephanie Sivell, Kathy Seddon, Helen Bulbeck, Annmarie Nelson, Melanie Calvert, Robin Grant, Richard Adams, Colin Watts, Olalekan Lee Aiyegbusi, Samantha Cruz Rivera, Pamela Kearns, Linda Dirven, Anthony Byrne
Journal: Neuro-Oncology (2022)

Abstract AIMS Trial registration supports unbiased reporting of research studies. Despite inconsistent use globally and sub-optimal completeness, registration is associated with publication of the same outcomes as defined in trial protocols, though these are not necessarily reported in published results. In the core outcomes in brain tumour trials (COBra) study a registry review was undertaken, alongside a systematic review of qualitative literature and semi-structured interviews, to develop a core outcome set (COS) outcome longlist. The study aims to identify all outcomes reported across all glioma trial registration data. METHOD Phase 3 interventional glioma trials involving patients aged 18 and over, registered on clinicaltrials.gov or the ISRCTN registry were included. Two researchers independently searched the databases and registered data and available protocols were retrieved. Two reviewers independently extracted basic trial data including primary and secondary outcomes. Outcomes were categorised according to an ontology developed through literature review. RESULTS 91 trials were identified. Primary outcome categories reported were survival (84%), disease activity (14%), symptoms (4%), adverse events (3%) and resource use (1%). Secondary outcome categories reported were survival (60%), adverse events (52%), quality of life (QoL, 41%), disease activity (30%), symptoms (20%), function (12%), resource use (7%), health status (7%), and economic (3%). The review contributed 15 unique outcomes to the final outcome longlist of 35. CONCLUSION Trial registries represent a pragmatic solution in COS development and enabled identification of outcomes not present in other data sources. Under half of registered glioma studies included QoL outcomes; a small minority included functional outcomes or economic evaluation.
Design of single-phased magnesium alloys with typically high solubility rare earth elements for biomedical applications: Concept and proof
Authors: Dong Bian, Xiao Chu, Jin Xiao, Zhipei Tong, He Huang, Qinggong Jia, Jianing Liu, Wenting Li, Hui Yu, Yue He, Limin Ma, Xiaolan Wang, Mei Li, Tao Yang, Wenhan Huang, Chi Zhang, Mengyu Yao, Yu Zhang, Zhigang Xu, Shaokang Guan, Yufeng Zheng
Journal: Bioactive Materials (2022)

Rare earth elements (REEs) have been long applied in magnesium alloys, among which the mischmetal-containing WE43 alloy has already got the CE mark approval for clinical application. A considerable amount of REEs (7 wt%) is needed in that multi-phased alloy to achieve a good combination of mechanical strength and corrosion resistance. However, the high complex RE addition accompanied with multiple second phases may bring the concern of biological hazards. Single-phased Mg-RE alloys with simpler compositions were proposed to improve the overall performance, i.e., "Simpler alloy, better performance". The single-phased microstructure can be successfully obtained with typical high-solubility REEs (Ho, Er or Lu) through traditional smelting, casting and extrusion in a wide compositional range. A good corrosion resistance with a macroscopically uniform corrosion mode was guaranteed by the homogeneously single-phased microstructure. The bimodal-grained structure with plenty of sub-grain microstructures allow us to minimize the RE addition to <1 wt%, without losing mechanical properties. The single-phased Mg-RE alloys show comparable mechanical properties to the clinically-proven Mg-based implants. They exhibited similar in-vitro and in-vivo performances (without local or systematic toxicity in SD-rats) compared to a high purity magnesium. In addition, metal elements in our single-phased alloys can be gradually excreted through the urinary system and digestive system, showing no consistent accumulation of RE in main organs, i.e., less burden on organs. The novel concept in this study focuses on the simplification of Mg-RE based alloys for biomedical purpose, and other biodegradable metals with single-phased microstructures are expected to be explored.
Current Medical Literature
Journal: JAMA (1901)

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